Oral drug delivery remains the most popular choice for drug delivery1, for the ease, convenience, and relative lack of pain during administration results in a high level of patient compliance. As a result, the majority of pharmaceutical dosage forms today are administered in the form of tablets, capsules, powders, granules, or liquids.
Despite their popularity, conventional oral dosage forms are not necessarily the most efficacious. Some patients, particularly geriatrics and pediatrics, have difficulty ingesting solid oral dosage forms2,3. This may be as a result of a variety of factors, ranging from the patient suffering from a condition that renders swallowing painful or difficult, to anginophobia (fear of choking)4,5 or due to the sometimes unpleasant taste. To combat this problem, a variety of rapid-dissolving drug delivery systems have been developed which dissolve in a patient's mouth within a few seconds to minutes of administration thus negating the need to chew or swallow6. These systems rely on high levels of disintegrants and/or effervescent agents to achieve their rapid-dissolving properties7. However, since most of these dosage forms are still formulated in tablet form, the abovementioned difficulty is still problematic.
Another obvious limitation to oral drug delivery exists in the form of the hostile environment presented by the gastro-intestinal tract (GIT) where significant quantities of the administered drug are lost due to acid hydrolysis and the hepatic ‘first pass’ effect8-13. In addition, not all drugs can be incorporated into oral dosage forms due to their specific physicochemical properties. Most importantly, solid oral dosage forms are impractical for the treatment of acute conditions, such as anaphylaxis, where a rapid pharmacological action is required. Drug release from solid oral dosage forms is not immediate since it has to first undergo disintegration and/or dissolution in the GIT prior to releasing the drug14.
In light of this, alternative routes of drug delivery are being sought. Much attention has been given to transmucosal drug delivery, specifically the buccal cavity, which boasts advantages over parenteral dosage forms without the associated caveats. This can be attributed to the direct drainage of blood from the buccal cavity into the internal jugular vein, thus bypassing the ‘first pass’ effect10, 13, 15, 16, and subsequently increasing the bioavailability of poorly bioavailable drugs. The relatively low level of enzymatic activity and a relatively stable pH in the buccal cavity also serves to provide a means for administrating sensitive drugs10,17. In addition, these drug delivery systems have a relatively high degree of patient compliance10.
In general, when the dosage form is placed in the mouth, contact with saliva causes it to disintegrate almost immediately into tiny particles, resulting in liberation of the drug. While still in the oral cavity, some of the drug is absorbed through the oramucosa. Further contact with saliva results in the particles dissolving into a drug loaded suspension. Subsequent swallowing of the remnants of the disintegrated dosage form results in more drug being pre-gastrically absorbed before its passage down the esophagus and into the stomach, where conventional drug absorption processes occur for oral dosage forms. This pre-gastric absorption results in increased bioavailability of the drug since the potentially destructive gastric environment and hepatic metabolism is bypassed. But perhaps the greatest benefit of the rapid disintegrating dosage form is that it combines the advantages of both liquid and conventional solid oral dosage forms. It provides the convenience of a tablet or capsule while simultaneously allowing for the ease of swallowing provided by a liquid formulation5,18-20.
Whilst much research is being conducted into developing transmucosal drug delivery systems with adequate mucosal tissue permeation, the real challenge lies in developing a system with the abovementioned benefits that is also capable of achieving rapid drug release.
Research interest has, to a great extent, focussed on porous materials or devices which can be described as those possessing characteristic pore and interconnecting structures which influence their function and performance. These materials possess unique properties which can find potential applications as biological tissue scaffolds, in controlled drug delivery, biomaterials engineering, life science and other scientific spheres21. These features include their (i) stable and porous configuration, (ii) high surface areas (iii) flexible pore sizes arranged in various distribution patterns and (iv) defined surface properties. These properties provide them with the potential to adsorb/load drug molecules and release them in a reproducible and predictable manner22.
As indicated above, conventionally, drugs are delivered to the body employing the predominant routes of administration such as oral delivery or injection. The intravenous route which provides rapid physiological relief of symptoms is associated with a high level of pain during administration and may lead to high drug concentrations being injected into the systemic circulation which can be fatal. The oral route of drug delivery offers several advantages in that it is more natural, less invasive and can be painlessly self-administered23. However, research has shown that after oral administration, numerous drugs are subject to extensive pre-systemic elimination by gastrointestinal degradation (due to the acidic conditions of the stomach or the presence of enzymes) and/or hepatic metabolism (i.e. the first-pass effect), and the resistance exerted by the intestine may result in low systemic bioavailability, shorter duration of therapeutic activity, and/or formation of inactive or toxic metabolites24-27.
To circumvent some of the above-mentioned limitations associated with the intravenous and oral routes, transmucosal drug delivery (i.e. delivery of drugs via absorptive mucosa in various easily accessible body cavities such as dermal, buccal, nasal or vaginal) has been explored as an alternative route of administering drugs28-30. The transmucosal route of administration also offers the potential for systemic absorption of drugs with plasma profiles closely mimicking that of an injection that makes them useful especially in emergency situations. In addition, mucosal membranes may also be useful sites with good accessibility for easy application of drug delivery systems, especially for those with bioadhesive qualities. With the development of transmucosal drug delivery systems having controlled drug release characteristics, the mucosa can be explored for the non-invasive systemic, sustained delivery of drugs31.
Thus far, the investigations on transmucosal drug delivery focused extensively on the use of formulations that are not actively porosity-enabled such as tablets, gels, hydrogels, micro-matrices, films, and pastes32-37. As far as we know, limited explorative studies exist on the development and mechanistic evaluation of porosity-enabled matrices employed for prolonged systemic drug delivery through mucosal sites. Porosity-regulated formulations can be described as superior to conventional formulations for transmucosal administrations in terms of their morphological flexibility (due to the presence of elastic pores) which can allow for easy manipulation of their drug loading efficiency and rate of drug delivery as well as enhance bioadhesion to mucosal sites and permeation enhancement for systemic delivery of drug molecules38,39. In recent years, the demand for such sophisticated approaches for the delivery of therapeutic agents has been on the increase40. Commonly existing porous drug delivery systems include: implants41, scaffolds42,43, hydrogels44, ceramics45-48, drug carriers49, biocomposites50, sponges51, microcapsules52, wafers53,55, membranes58,57 and nanoparticles58 for various biomedical applications.
In this specification the following terms have the following meanings and the specification and claims should be construed accordingly:
“Multi-configured” when used in conjunction with a pharmaceutical dosage form means that the dosage form has at least two release rate controlling upper and lateral surfaces of varying geometries in their lateral and/or axial planes that are adjacent to each other or a third layer, the said layers preferably being discoid in shape.
“Pore-regulated” when used in conjunction with a pharmaceutical dosage form means that the dosage form is able to modulate the rate of release of an active pharmaceutical compound or compounds on the basis of the size, and/or extent and/or distribution of pores introduced, or formed as a result in the matrix or matrices of the pharmaceutical dosage form.
“Monolithic” when used in conjunction with a pharmaceutical dosage form means that the pharmaceutical dosage form comprises a single polymeric matrix layer in which one or more active pharmaceutical compounds are homogeneously dispersed.
“Heterogeneous” when used in conjunction with a pharmaceutical dosage form means that the dosage form comprises a plurality of layers, preferably two, in which an active pharmaceutical compound or compounds are homogenously dispersed in each layer or in a single layer only.